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J Biol Chem, Vol. 275, Issue 16, 12136-12146, April 21, 2000

The Lipophilicity of Phorbol Esters as a Critical Factor in Determining the Pattern of Translocation of Protein Kinase C  Fused to Green Fluorescent Protein^*

Qiming J. Wang, Tzan-Wei Fang, David Fenick, Susan Garfield^§, Bruno Bienfait^¶, Victor E. Marquez^¶, and Peter M. Blumberg

From the  Molecular Mechanisms of Tumor Promotion Section, Laboratory of Cellular Carcinogenesis and Tumor Promotion, ^§ Laboratory of Experimental Carcinogenesis, and ^¶ Laboratory of Medicinal Chemistry, NCI, National Institutes of Health, Bethesda, Maryland 20892

Our previous study showed differential subcellular localization of protein kinase C (PKC)  by phorbol esters and related ligands, using a green fluorescent protein-tagged construct in living cells. Here we compared the abilities of a series of symmetrically substituted phorbol 12,13-diesters to translocate PKC . In vitro, the derivatives bound to PKC with similar potencies but differed in rate of equilibration. In vivo, the phorbol diesters with short, intermediate, and long chain fatty acids induced distinct patterns of translocation. Phorbol 12,13-dioctanoate and phorbol 12,13-nonanoate, the intermediate derivatives and most potent tumor promoters, showed patterns of translocation typical of phorbol 12-myristate 13-acetate, with plasma membrane and subsequent nuclear membrane translocation. The more hydrophilic compounds (phorbol 12,13-dibutyrate and phorbol 12,13-dihexanoate) induced a patchy distribution in the cytoplasm, more prominent nuclear membrane translocation, and little plasma membrane localization at all concentrations examined (100 nM to 10 µM). The highly lipophilic derivatives, phorbol 12,13-didecanoate and phorbol 12,13-diundecanoate, at 1 µM caused either plasma membrane translocation only or no translocation at incubation times up to 60 min. Our results indicate that lipophilicity of phorbol esters is a critical factor contributing to differential PKC  localization and thereby potentially to their different biological activities.

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^* The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Bldg. 37, Rm. 3A01, NCI, National Institutes of Health, 37 Convent Dr. MSC 4255, Bethesda, MD 20892-4255. Tel.: 301-496-3189; Fax: 301-496-8709; E-mail: blumberp@dc37a.nci.nih.gov.

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Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.

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